Methods for treating scars and aging skin

ABSTRACT

Beneficial topical compositions for treating scar or aging skin are provided. In one embodiment, the compositions include  Bulbine frutescens, Centella asiatica  and a phenol derived from olives, such as oleuropein. The composition may be used in the treatment of scars formed during surgery. The composition may also be used cosmeceutically in the treatment of aged skin, and may include phosphatidylserine, vitamins, and other beneficial anti-aging ingredients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/935,686, filed Nov. 9, 2015, which is a continuation of U.S. patentapplication Ser. No. 13/294,957, filed on Nov. 11, 2011, which is acontinuation of U.S. patent application Ser. No. 13/294,116, filed Nov.10, 2011, now U.S. Pat. No. 8,591,961, which is a continuation-in-partof U.S. patent application Ser. No. 12/554,364, filed Sep. 4, 2009, nowU.S. Pat. No. 8,071,139, which claims priority from U.S. PatentApplication Ser. No. 61/094,170, filed Sep. 4, 2008 and from SouthAfrican Patent Applications Nos. 2008/08004 and 2009/04000 filedrespectively on Sep. 18, 2008 and Jun. 8, 2009, all herein incorporatedby reference.

BACKGROUND Field

Several embodiments of the invention relate to the treatment of skin. Inone embodiment, the invention comprises beneficial topical compositionsfor preventing skin damage and for treating skin that has already beendamaged. Damaged skin includes, but is not limited to, photoaged skin,inflamed skin, acne, burns, wounds, age spots, stretch marks, wrinkles,and scars that result from such damage.

Description of Related Art

In U.S. Pat. No. 6,159,494 to Widgerow and Chait, herein incorporated byreference, a method of treating damaged human skin is disclosed. Thetreatment includes applying to the skin a medicament for topicalapplication (such as an ointment) comprising as the active ingredientsBulbine frutescens and, optionally, Centella asiatica. The medication isused in conjunction with a tape that is applied to the skin about thescar to, for example, prevent or minimize any tension that is applied tothe scar.

SUMMARY

In several embodiments, a composition for effectively treating damagedskin is provided. The skin may have a wound or may exhibit one or moresigns of aging. Damaged skin includes, but is not limited to, scars,photoaged skin, inflamed skin, acne, burns, wounds, age spots, stretchmarks, wrinkles, dull skin, pores, hyperpigmentation, andhypopigmentation. Thus, in many embodiments, the topical compositionsdescribed herein rejuvenate, revitalize and heal the skin.

In one embodiment, the composition comprises a topical composition(e.g., a gel medicament) that comprises, consists essentially of, orconsists of at least one extract of Bulbine frutescens in an amount fromabout 0.25% to about 25% mass per mass of the composition, at least oneextract of Centella asiatica in an amount from about 0.1% to about 25%mass per mass of the composition, and one or more phenols (including,but not limited to compounds extracted from olives and/or olive leaf) inan amount from about 0.1% to about 10% mass per volume of thecomposition. In one embodiment, the phenol comprises oleuropein. In someembodiments, the composition further comprises one or more of thefollowing: a silicone (e.g., dimethicone), water, a solvent, apreservative, a surfactant, a gelling agent, and a pH balancer.Phosphatidylserine or other phospholipids are included in someembodiments. One or more vitamins are included in several embodiments.In some embodiments, growth factors and/or stem cells are included. Insome embodiments, the topical composition comprises at least one extractof Bulbine frutescens in an amount from about 1.25 mg to 25 mg, at leastone extract of Centella asiatica in an amount from about 0.5 mg to 25mg, and at least one extract of olive (e.g., from the olive fruit orleaf, such as oleuropein) in an amount from about 0.5 mg to 2.5 mg, andoptionally dimethicone and/or phosphatidyl serine. In severalembodiments, the topical composition comprises one or more Bulbine,Centella, and glycosides.

In one embodiment, the invention comprises a gel medicament for topicalapplication to damaged skin, said medicament comprising, consisting orconsisting essentially of an extract of Bulbine frutescens in an amountfrom about 9% to about 11% mass per mass of the medicament, an extractof Centella asiatica in an amount from about 0.1% to about 2% mass permass of the medicament, a phenol (e.g., oleuropein) extracted from asource selected from the group consisting of olive leaf and olive oil inan amount from about 0.18% to about 0.3% mass per volume of themedicament, dimethicone, water, and one or more of the following:propylene glycol, glycerol-polyethylene glycol oxystearate, poloxamer,and phenoxyethanol. Phosphatidylserine is included in some embodiments.

In several embodiments of the invention, a method for treating damagedskin is provided. In one embodiment, the method comprises identifyingdamaged skin and applying a topical composition to said damaged skin,wherein application of said topical composition treats said damagedskin. The topical composition may comprise any of the variousembodiments described herein, and in one embodiment, includes one ormore extracts of Bulbine frutescens, one or more extracts of Centellaasiatica, oleuropein (and/or other olive-related compound), andoptionally one or more silicones. Anti-aging ingredients may be includedin several embodiments.

In several embodiments, the damaged skin is damaged by a wound, a scar,acne, inflammation, stretching of skin (such as with pregnancy, surgery,or weight gain), or aging. In one embodiment, the wound is producedduring a surgical procedure. In one embodiment, the application of thecomposition to the damaged skin reduces inflammation. In one embodiment,the topical application of the composition to the damaged skinunexpectedly produces an occlusive dressing without the use ofmicroporous tape. In one embodiment, the composition facilitatesformation of a barrier that protects the damaged skin from environmentalinfluences and provides support for the damaged skin. In severalembodiments, the beneficial combination of Bulbine, Centella andoleuropein (and/or other olive-related compound) works synergistically,and has several advantages over a combination of Bulbine and Centellaalone.

In several embodiments, the invention comprises a topical compositionfor the treatment of damaged skin, comprising one or more extracts ofBulbine frutescens, one or more extracts of Centella asiatica, one ormore olive extracts, and, optionally, one or more silicones. The oliveextract comprises oleuropein in one embodiment. The silicone maycomprise dimethicone. In one embodiment, extracts of Bulbine frutescensare provided in a range of about 0.25% to about 25% mass per mass of thetopical composition, extracts of Centella asiatica are provided in arange of about 0.1% to about 10% mass per mass of the topicalcomposition, and olive extracts are provided in a range of about 0.1% toabout 5% mass per volume of the topical composition.

In several embodiments, the topical composition is in the form of a gel,cream or ointment. In one embodiment, the topical composition furthercomprises at least one ingredient selected from the group consisting ofwater, a solvent, a preservative, a surfactant, a gelling agent, and apH balancer. In one embodiment, all of these ingredients are combinedwith Bulbine, Centella, and olive extracts.

In some embodiments, the topical composition further comprises at leastone ingredient selected from the group consisting of phospholipids,amino acids, vitamins and peptides. In one embodiment, the topicalcomposition includes phosphatidylserine.

In several embodiments, the topical composition is used to treat damagedskin. Damaged skin includes, but is not limited to, wounded skin,scarred skin, and aging skin. Damaged skin may have age spots, stretchmarks, wrinkles, or combinations thereof. Damaged skin may exhibitlaxity.

In some embodiments, the topical compositions described herein are usedwithout the use of microporous tape or other support structure. In oneembodiment, the topical compositions are sufficiently viscous or stickyto produce an occlusive dressing without a support structure. In severalembodiments, a topical composition is applied beneath a supportstructure (e.g., tape). In other embodiments, a topical composition isapplied on top of a support structure (e.g., tape). In one embodiment,the tape is a microporous tape that is designed to accept the topicalcomposition on the outer surface of the tape and deliver the topicalcomposition in contact with the damaged skin through, for examples,pores or other conduits. In yet other embodiments, a user is instructedto apply a topical composition both below and on top of a supportstructure (e.g., tape).

In several embodiments, the topical compositions are provided in adelivery device (such as a multi-chambered device) that separates one ormore ingredients from other ingredients. For example, the Bulbine,Centella, olive extracts and/or silicone may be separated from one ormore additional ingredients in a dual-chambered device. The topicalcompositions may be applied daily or on an as needed basis. Individualingredients may be applied either simultaneously or sequentially.

DETAILED DESCRIPTION

Several embodiments of the invention comprise an effective compositionfor preventing skin damage and for treating skin that has already beendamaged. Damaged skin includes scars, photoaged skin, inflamed skin,acne, burns, wounds, age spots, stretch marks, wrinkles, dull skin,pores, hyperpigmentation, and hypopigmentation. In several embodiments,the topical composition comprises one or more extracts of Bulbinefrutescens, Centella asiatica, olive extract (e.g., olive oil, oliveleaf extract) and, optionally, one or more silicones. Anti-agingingredients, such other plant extracts, phospholipids, vitamins,minerals, peptides, amino acids, growth factors, essential oils, andstem cells are further included in several embodiments.

Bulbine

In several embodiments, the invention comprises one or more extracts ofBulbine. Extracts may be obtained from any part of the plant, includingthe leaves, stems, flowers, fruits, bark, and roots. Bulbine frutescensis a common garden plant that is native to South Africa. In severalembodiments of the invention, the use of Bulbine frutescens isparticularly advantageous because of its hydrating properties. Inseveral embodiments, one or more glycoproteins from Bulbine frutescensare sufficiently large to remain on the surface of the skin long enoughto produce effective hydration of the skin. Additionally, in someembodiments, the extracts (e.g., peptides or other compounds) of Bulbinefrutescens have decorin-like effects on wound healing, and improvemature collagen deposition in healing wounds. In some embodiments,compositions comprising Bulbine are especially effective because one ormore polypeptides mimic the effect of decorin and rearrange collagen ina uniform manner during the process of fibrillogenesis and collagenregeneration. In some embodiments, the use of Bulbine, Centella, andolive extracts (e.g., Bulbine frutescens, Centella asiatica, andoleuropein) is effective in modulating, uniformly arranging, andmaturing collagen during the process of healing. Thus, in someembodiments, the topical composition not only stimulates new collagenformation, but packages the new fibres in a uniform and structuredmanner. In one embodiment, the topical compositions disclosed hereincontain agents that affect decorin activity or mimic decorin tofacilitate collagen remodeling and structural arrangement.

Centella

Centella asiatica is a small herbaceous annual plant. Extracts, such asasiaticosides, asiatic acid and triterpenes, may be obtained from anypart of the plant, including the leaves, stems, flowers, fruits, bark,and roots. In several embodiments, the invention comprises one or moreextracts of Centella asiatica, or other Centella species. In oneembodiment, Centella asiatica is used to decrease inflammation,stimulate type 1 collagen production, and/or act as anti-oxidant.

In one embodiment, compositions comprising Centella are used in scarmanagement. In some cases, the more quickly a scar matures the lesschance there is of hypertrophy. Collagen maturation goes through phaseswith collagen type III being present in greater levels in the earlyscarring phase. As the scar matures the ratio of type III to type Ireturns to normal levels. Thus, in several embodiments, the inventioncomprises one or more ingredients that encourages type I collagenformation. In some embodiments, one or more extracts of Centellaasiatica increase levels of mature collagen and facilitate normalizationof collagen ratios. In several embodiments, purified extracts(triterpenic fractions, including asiaticoside and other saponins) ofthe Centella plant are used.

TGFβ is the prototype of a protein superfamily that has been recognisedas a fibroproliferative and collagen stimulating agent involved inexcess scarring (particularly TGF-β1). Many isoforms of the proteinexist with most isoforms sharing the same fibroproliferative properties.One isoform, TGF-β3 however, appears to have a protective effect againstexcess collagen formation counteracting the TGF-β1 effects. According toone embodiment, asiaticoside can down-regulate TGF-β1 mRNA and TIMP1expressions and upregulate TGF-β3 mRNA expression in post burnhypertrophic scars, and is also capable of decomposing the products oftype I collagen, contributing to the reduction of hypertrophic scarformation. Thus, in several embodiments, the invention comprises one ormore agents (such as asiaticoside) to modulate TGFβ activity.

Olive Extracts

In several embodiments, the invention comprises one or more extracts ofolive (e.g., olive oil, olive leaf extract, etc.). Extracts include, inseveral embodiments, phenolic compounds. Extracts, which may or may notbe in the form of oil (or derived from an oil), may be obtained from anypart of the olive tree including the leaves, stems, flowers, fruits,bark, and roots. In one embodiment, the invention comprises, consistsessentially of or consists of Bulbine, Centella and an olive extract(e.g., oleuropein). In one embodiment, oleuropein and other agents maybe extracted from the leaves of the olive tree. In some embodiments,engineered or synthesized phenols may be used in the compositionsdescribed herein. In some embodiments, oleuropein and/or additionalconstituents provide for a multimodality approach to scar managementcovering all phases of the wound healing cascade. For example, forcertain scar applications, an important physiologic response to woundingis that of inflammation. Inflammation can also be one of the mostdestructive: over exuberant inflammation is thought to be cause of mostchronic arthritic conditions, heart disease, and chronic woundpathogenesis. Along the physiologic path to scar formation, excessinflammation will result in an exaggerated scar. Suture materials arefrequently associated with this phenomenon. On the other hand,controlled inflammation may speed up the process of scar maturation withminimal fibrosis. Thus, in several embodiments, the invention provides atherapeutic balance by facilitating controlled inflammation (e.g., byachieving a balance between no inflammation and excess inflammation).Thus, surprisingly, in several embodiments, the compositions disclosedherein maintain a certain amount of inflammation to ensure optimalhealing.

Phenols (e.g., oleuropein, oleocanthal) extracted from olives have knownanti-inflammatory and antibacterial properties. In several embodiments,the invention comprises low doses of one or more phenols (whetherextracted from the olive plant or not) in combination with Bulbinefrutescens and Centella asiatica such that helpful inflammation isunaffected, whereas exuberant inflammation, typical of foreign bodyreactions, is down-regulated or modulated. In some embodiments, theinvention comprises one or more Bulbine, Centella, and glycosides(including, but not limited to, oleuropein).

In several embodiments of the invention, the topical compositionsdescribed herein include one or more extracts of olive, which are usedto achieve controlled inflammation. It is well-accepted that ongoinginflammation retards wound healing. This is especially important inchronic non-healing wounds where proteases and reactive oxygenmetabolites are responsible for much on the ongoing damage,antiproliferative effects, and non-healing seen in these wounds. Thenegative effects of exuberant inflammation are not limited to chronicwounds: in acute wounds low-grade ongoing inflammation results inincreased matrixmetalloproteinase and cytokine elaboration (especiallyTGF-β1 and 2, Il-1,6,8) and a profibrotic state with a resultantexaggerated scar. This inflammation can be initiated by tension on thescar, foreign material (long-standing subcuticular sutures), bacteria,biofilm, and many other scenarios. Thus, control of inflammation duringthe healing phase is a desired goal of several embodiments of theinvention. In several embodiments of the invention, at least one oliveextract is provided. Olive extracts, such as olive oil (e.g., newlypressed extra-virgin olive oil) and extracts of olive leaf, containphenolic compounds (oleocanthal, oleuropein) that act as a naturalanti-inflammatory compound that has a potency and profile strikinglysimilar to that of ibuprofen, without the undesired side effects.Although structurally dissimilar, both these molecules inhibit the samecyclo-oxygenase enzymes in the prostaglandin-biosynthesis pathway.According to several embodiments, this anti-inflammatory effect hasimportant implications for scar control. Thus, in several embodiments,the topical composition inhibits cyclo-oxygenase enzymes. In severalembodiments, olive extracts include one or more of the following:hydroxytyrosol, oleocanthal, oleuropein, rutin, apigenin, and luteolin.

In several embodiments, olive extracts are used to stimulate proteasomefunction and promote normal fibroblast (reverses senescence) activitywith formation of new collagen. Proteasomes “mop up” fragmented proteinparticles including fragmented collagen, thereby minimizing theformation of undesired clumped collagen.

Silicone

In several embodiments, the invention comprises one or more silicones.In some embodiments, the invention comprises, consists essentially of,or consists of one or more extracts of Bulbine, Centella, phenols or anolive extract, and silicone. Silicones include, but are not limited todimethicone and cyclomethicones. In one embodiment, the silicone iseither in the form of sheeting or a gel. In one embodiment, thesilicone, when used in conjunction with Bulbine frutescens and Centellaasiatica, provides a synergistic complement to the action of Bulbinefrutescens as a hydrating agent. In one embodiment, dimethicone is addedto the mix as an extremely efficient hydrating agent complementing theaction of Bulbine frutescens. In some embodiments, the addition of anolive extract with silicone results in a beneficial sticky barrier.

Normal skin has a mature stratum corneum characterised by minimaltransepidermal water loss. Dehydration of the stratum corneum initiatessignaling to keratinocytes. These keratinocytes are stimulated toproduce cytokines which activate dermal fibroblasts to synthesize andrelease collagen. Excessive collagen production may lead to abnormalscarring. In one embodiment of the invention, silicone is provided as aneffective barrier to water loss and stratum corneum breach. Silicone maybe provided in the form of sheeting, gels (e.g., dimethicone), or otherappropriate forms.

Phosphatidlyserine

In several embodiments, the topical compositions comprisephosphatidylserine. In the context of collagen modulation, particularlywhen considering anti-aging intervention, the Bulbine, Centella, anolive extract (e.g., oleuropein), and optionally silicone, may be usedin conjunction with phosphatidylserine. In one embodiment,phosphatidylserine stimulates the formation of procollagen, a collagenprecursor. This new collagen is then acted on by the combination ofBulbine, Centella, and olive extract(s), and/or other optionalingredients, to induce maturation of the collagen. In one embodiment,this sequence has important synergistic anti-aging benefits in severalembodiments. In one embodiment, phosphatidylserine also decreasesmatrixmetallproteinase 1 (MMP1) levels which promotes collagen andextracellular matrix breakdown characteristic of photodamaged skin. Itthen stimulates the formation of new collagen by promoting procollagenformation.

Examples of Additional Ingredients & Ranges

In several embodiments, the topical compositions comprise one or moreadditional ingredients. These additional ingredients, along withBulbine, Centella, olive extracts, silicone, and phosphatidylserine, areprovided in a range of about 0.1% to about 50%, or higher, according toseveral embodiments (e.g., 0.1%-1%, 1%-2%, 2%-5%, 5%-10%, 10%-25%,25%-50%, and overlapping ranges thereof). As with other percentagesdisclosed herein, these percentages may be mass per mass, mass tovolume, or volume to volume with respect to the total composition. Insome embodiments, the ingredients of the topical compositions disclosedherein are provided in amounts ranging from about 1 μg to about 1 g, orhigher (e.g., 1 μg-2 μg, 2 μg-5 μg, 5 μg-10 μg, 10 μg-25 μg, 25 μg-100μg, 100 μg-500 μg, 500 m-1 mg, 1 mg-5 mg, 5 mg-10 mg, 10 mg-20 mg, 20mg-30 mg, 30 mg-40 mg, 40 mg-50 mg, 50 mg-60 mg, 60 mg-70 mg, 70 mg-80mg, 80 mg-90 mg, 90 mg-100 mg, 100 mg-250 mg, 250 mg-500 mg, 500 mg-1 g,or higher, and overlapping ranges thereof). These amounts may be theweight of the ingredient per individual application (or dose), per unitor per container (tube, bottle, jar, etc.). Individual applications maybe made hourly, 1-10 times per day, weekly, or as needed.

For example, in some embodiments, one or more of the followingingredients are included, along with extracts of Bulbine, Centella,olive, and optionally silicone and/or phosphatidylserine: other plantextracts and vitamins or provitamins for the purpose of formulating acomprehensive cosmetic skin maintenance range achieving cleansing,moisturizing, healing, toning, hydrating, and protecting the skin. Theseextracts, vitamins and provitamins include, but are not limited to:Symphytum officinale, provitamin B5, Hamamelis virginiana, Cucumissativus, zinc, Enantia chlorantha, German camomile (bisabolol), retinylpalmitate, Macrocystis pyrifera, prolamines, and Imperata cylindrica,white tea-leaf extract, Calcium α-hydroxymethionine, homotaurine,matrikines, hydrosolanum, and hesperidum.

In some embodiments, the composition includes one or more plant extracts(such as Bulbine) combined with one or more of the following: one ormore Centella extracts, one or more olive extracts, phospholipids (e.g.,phosphatidylserine), vitamins (e.g., vitamin A, B, C, and/or D),minerals (e.g., calcium, magnesium, and copper), acids (e.g., hyaluronicacid, salicylic acid, (mandelic acid, and fruit acids), cells orcellular extracts, fats or oils (e.g., shea butter, argan oil, andcoconut oil), fruit extracts (e.g., citrus, acai, goji, blueberry, andacerola), caffeine, green tea extracts, essential oils, enzymes, andcoenzymes (e.g., ubiquinone).

The active compounds described herein may be formulated foradministration in a pharmaceutical carrier in accordance with knowntechniques. See, e.g., Remington, The Science And Practice of Pharmacy(9^(th) Ed. 1995), herein incorporated by reference. In the manufactureof a composition according to several embodiments of the invention, theactive compound (including the physiologically acceptable salts thereof)may be admixed with, inter alia, an acceptable carrier. The carrier isacceptable in the sense of being compatible with any other ingredientsin the composition and must not be deleterious to the patient. Thecarrier may be a solid or a liquid, or both, and may be formulated withthe compound as a unit-dose formulation, for example, a tablet, whichmay contain from 0.01% or 0.5% to 95% or 99% by weight of the activecompound. One or more active compounds may be incorporated in thecompositions of the invention, which may be prepared by any of thewell-known techniques of pharmacy comprising admixing the components,optionally including one or more accessory ingredients. Carriers whichmay be used include petroleum jelly, lanoline, polyethylene glycols,alcohols, transdermal enhancers, and combinations of two or morethereof. In some embodiments, the topical composition is partially orfully incorporated in delivery vehicles such as microspheres ornanoparticles, or are encapsulated (e.g., in liposomes). In someembodiments, a topical composition is pre-impregnated in/on a supportstructure (e.g., tape, patch, bandage, etc.).

In addition to one or more active compounds, the topical compositionsdisclosed herein comprise other additives, such as pH-adjustingadditives. In some embodiments, useful pH-adjusting agents includeacids, such as citric acid or lactic acid, bases or buffers, such assodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodiumborate, or sodium gluconate.

The compositions may contain antimicrobial preservatives in someembodiments. In several embodiments, antimicrobial preservativesinclude, but are not limited to, methylparaben, propylparaben, benzylalcohol, ethylhexylglycerin, potassium sorbate, phenoxyethanol, EDTA,grapefruit seed extract, tea tree oil, sodium benzoate, dehydroaceticacid, and combinations thereof. In some embodiments, anti-fungalpreservatives are used alone or in combination with anti-bacterialpreservatives. In one embodiment, the topical compositions areparaben-free. In one embodiment, an antimicrobial preservative is usedwhen the formulation is placed in a vial designed for multi-dose use. Insome embodiments, the compositions disclosed herein compriseanti-biofilm anti-microbial agents such as lactoferrin, xylitol,farnesol gallium, dispersin B, EDTA, and furanone compounds, orcombinations thereof. In one embodiment, the composition comprisesBulbine, Centella, olive extract (e.g., oleuropein) and one or moreanti-biofilm agents. The compositions according to some embodiments maybe lyophilized using techniques well known in the art.

In several embodiments, the topical compositions disclosed hereincomprise agents that stimulate production of extracellular matrixcomponents. These agents include, but are not limited to, matrikines,peptides and their lipophilic derivatives, plant extracts, and polyols.Specific ingredients include one or combinations of the following asexamples: Centella asiatica, niacinamide, tetrahexyldecyl ascorbate,palmitoyl tetrapeptide-5, palmitoyl oligopeptide, palmitoyltetrapeptide-7, palmitoyl dipeptide-5, diaminobutyroyl hydroxythreonine,Siesgeseckia orientalis, Rabdosia rubescens, rice extract, olive oil,jojoba oil, Pichia pastoris, resveratrol, tripeptide-10 citrulline,acetyl dipeptide-1 cetyl ester, and phosphatidylserine, and extracts orsalts/acids thereof. One or more of these ingredients are combined witha Bulbine extract in several embodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that decrease the degradation of extracellular matrixcomponents. The agents include, but are not limited to, plant extracts,vitamins, and peptides. Specific ingredients include one or combinationsof the following as examples: blackberry leaf, Centella asiatica,tetrahexyldecyl ascorbate, Siesgeseckia orientalis, Rabdosia rubescens,Actinidia chinensis, Sophora augustifolia, dipalmityl hydroxyproline,glycine soya protein, and phosphatidylserine, and extracts orsalts/acids thereof. One or more of these ingredients are combined witha Bulbine extract and/or an olive extract in several embodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that improve fibroblast adhesion to extracellularmatrix, including, but not limited to, yeast extract, peptides, andplant extracts. Specific ingredients include one or combinations of thefollowing as examples: Pichia pastoris, hexapeptide-10, and Bulbine, andextracts or salts/acids thereof. One or more of these ingredients arecombined with a Centella extract and/or an olive extract in severalembodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that alter melanin production and distribution,including, but not limited to, vitamins, plant extracts, aldehydes,glycosides, and peptides. Specific ingredients include one orcombinations of the following as examples: niacinamide, tetrahexyldecylascorbate, alpha arbutin, Siesgeseckia orientalis, Rabdosia rubescens,Actinidia chinensis, Sophora augustifolia, pomegranate, and extracts orsalts/acids thereof. One or more of these ingredients are combined witha Bulbine extract, Centella extract and/or an olive extract in severalembodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that improve barrier structure and function, including,but not limited to, polyols, ceramides, sterols, plant extracts,peptides. Specific ingredients include one or combinations of thefollowing as examples: xylitylglucoside, anhydroxylitol, xylitol,ceramide 2, ceramide 3, hydroxypropyl bispalmitamide MEA, glycine soyasterols, niacinamide, Bulbine, and extracts or salts/acids thereof. Oneor more of these ingredients are combined with a Centella extract and/oran olive extract in several embodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that reduce glycation, including, but not limited to,plant extracts, vitamins, peptides. Specific ingredients include one orcombinations of the following as examples: Centella Asiatica, vitaminB-6, and L-carnosine, and extracts or salts/acids thereof. One or moreof these ingredients are combined with a Bulbine extract and/or an oliveextract in several embodiments.

In several embodiments, the topical compositions disclosed hereincomprise agents that improve skin hydration, including, but not limitedto, amino acids, polyols, plant extracts, vitamins, and saccharides.Specific ingredients include one or combinations of the following asexamples: Bulbine, xylitylglucoside, anhydroxylitol, xylitol, betaine,and niacinamide, and extracts or salts/acids thereof. One or more ofthese ingredients are combined with a Centella extract and/or an oliveextract in several embodiments.

In several embodiments, the topical compositions disclosed hereincomprise antioxidants. In one embodiment, antioxidants are useful formodulating appropriate collagen crosslinking. Linkages need to besusceptible to MMP breakdown to ensure balanced degradation andneosynthesis. Pyridinoline crosslinks, not normally seen in skin, may beundesired because they are able to withstand major force and tend to beresistant to MMP-1 degradation. This pyridinoline phenomenon has beenlinked to oxygen radical activity (especially in burns); thus,antioxidants appear to be beneficial in potential scar reductionaccording to several embodiments. Antioxidants useful in severalembodiments include, but are not limited to, superoxide dismutase,catalase, glutathione peroxidase, glutathione, ascorbic acid, andtocopherol. In several embodiments, extracts of Centella asiatica andolive (e.g., oleuropein) are used as antioxidants.

In several embodiments, the topical compositions disclosed hereincomprise anti-bruising agents. Such agents include, but are not limitedto, arnica. Agents or devices that modulate the temperature of thetarget tissue are provided in some embodiments, and may also help withbruising.

In several embodiments, the topical compositions disclosed hereincomprise agents or devices that modulate extracellular shear forcepressure on the inside of the wound. In one embodiment, by decreasinghydrostatic, osmotic, and therefore internal fluid shear forces, lesstension is generated on the wound intrinsically. Thus, in someembodiments, hygroscopic agents are included in the compositionsdisclosed herein. Hygroscopic agents include, but are not limited to,honey, carboxymethylcellulose, glycerol, sugar, aloe vera powder, andother ingredients that, for example, sequester or absorb fluid from thedamaged tissue.

In one embodiment, the composition comprises a topical composition(e.g., a gel medicament) that comprises, consists essentially of, orconsists of an extract of Bulbine frutescens in an amount from about0.25%-25% (e.g., 5%, 9% or 9.9% to about 11%) mass per mass of thecomposition; an extract of Centella asiatica in an amount from about0.01%-10% (e.g., 0.1%-2%) mass per mass of the composition; a phenol(e.g., extracted from the olive fruit, leaf, etc.) in an amount fromabout 0.01%-5% (e.g., 0.18%-0.3%) mass per volume of the composition. Insome embodiments, the phenols comprise about 0.18% to 0.3% mass/volumeof the medicament when used for the treatment of damaged skin such asskin cut in an operation and about 0.018% to 0.03% when the compositionis used for cosmetic purposes. In one embodiment, the Centella asiaticamay comprise from about 0.45% to 0.55% (e.g., about 0.5%) mass per massof the composition.

In several embodiments, the invention comprises, consists essentiallyof, or consists of a topical composition comprising one or more extractsof Bulbine, one or more extracts of Centella, phenols or one or moreolive extracts, and silicone. In one embodiment, the topical compositioncomprises, consists essentially of, or consists of Bulbine frutescensextract, Centella asiatica extract, oleuropein, and dimethicone. Inseveral embodiments, the ingredients are provided in the followingamounts: one or more extracts of Bulbine at about 0.25% to 75%, one ormore extracts of Centella at about 0.11% to 50%, phenols or one or moreolive extracts at about 0.1% to 40%, and silicone at about 0.1% to 20%.Percentages can be mass/mass, volume/volume, or mass/volume.

In several embodiments, the topical composition may comprise, consistessentially of, or consist of two or more of the following: (i) Bulbine(e.g., Bulbine frutescens extract), (ii) Centella (e.g., Centellaasiatica extract), (iii) at least one olive extract (e.g., oleuropein orother phenol), (iv) at least one silicone, and (iv) at least one apharmaceutically acceptable carrier, wherein the ingredients areprovided in an amount from about 0.0001, 0.001, 0.01, or 0.1% by weightto about 1, 2, 5 or 10% by weight, or up to 90, 95 or 99% by weight(e.g., in some embodiments, at least about 0.1%, 1%, 5%, 10%, or 15%).

In several embodiments, the topical composition may comprise, consistessentially of, or consist of two or more of the following: (i) at leastone Bulbine frutescens extract (ii) at least one Centella asiaticaextract, (iii) at least one extract from olive oil or olive leaf, (iv)at least one silicone, (v) at least one gelling agent, (vi) at least onepH-balancing agent, (vii) at least one solvent, and (viii) at least onepreservative, wherein the ingredients are provided in an amount fromabout 0.001% by weight to about 95% percent by weight (e.g., 0.1%-5%,5%-10%, 10%-15%, 15-20%, 20%-25%, 25%-50%, or 50%-75%, or overlappingranges thereof). The non-active ingredients may be varied as desired asmay the proportions of such ingredients. The proportions of the activeingredients may be also be varied. For example, in one embodiment, theamount of Centella asiatica is provided in the range of between about0.1% and 0.25% to produce a milder medicament where the goal is texturemodification, e.g. when treating skin that is damaged as a result ofaging or damage by excessive exposure to ultra violet light, or whenpreventing damage. In one embodiment, the oleuropein content will bereduced by a factor of ten (to e.g., 0.018 to 0.03% mass to volume ofthe final preparation of the topical composition) for use as a cosmetic.In many embodiments, higher concentrations of Centella extracts areused, even for preventative or daily cosmetic uses.

In several embodiments, the topical composition may comprise, consistessentially of, or consist of two or more of the following ingredients:0.10-5.0% Centella Asiatica extract, 0.25-5.0% Bulbine Frutescensextract, 0.10-0.50% of a phenol extracted from an olive extract (e.g.,oleuropein), and 0.10-5.0% phosphatidylserine. In alternativeembodiments, the topical composition may also comprise, consistessentially of, or consist of one or more of the following ingredientslisted on Table 1 in addition to, or instead of, the ingredients listedabove.

TABLE 1 Pyridoxine Tris-Hexyldecanoate—0.25-5.0% TetrahexyldecylAscorbate—0.25-5.0% Niacinamide—0.50%-5.0% Hexapeptide-10—0.0001-1.0%(pure peptide basis) Acetyl Dipeptide-1 Cetyl Ester—0.0001-1.0% (purepeptide basis) Tocotrienol—0.05-3.0% DipalmitoylHydroxyproline—0.20-5.0% Palmitoyl Tripeptide-5—0.0001-1.0% (purepeptide basis) Pamitoyl Oligopeptide—0.0001-1.0% (pure peptide basis)Palmitoyl Tetrapeptide-7—0.0001-1.0% (pure peptide basis) PalmitoylDipeptide-5 Diaminobutyroyl Hydroxythreonine— 0.0001-1.0% (pure peptidebasis) Palmitoyl Dipeptide-5 Diaminohydroxybutyrate—0.0001- 1.0% (purepeptide basis) Siegesbeckia Orientalis Extract—0.25-5.0% RabdosiaRubescens Extract—0.25-5.0% Actinidia Chinensis (Kiwi) Fruit Water v0.25-5.0% Sophora Angustifolia Root Extract—0.25-5.0% Helianthus Annuus(Sunflower) Seed Oil—0.25-5.0% Lupinus Albus Seed Extract—0.25-5.0%Glycine Soja (Soybean) Protein—0.25-5.0% Oryza Sativa (Rice)Extract—0.25-5.0% Artemia Extract—0.25-5.0% Hydrolyzed RiceExtract—0.25-5.0% Simmondsia Chinensis ( Jojoba) Seed Extract—0.25-5.0%Blackberry Leaf Extract—0.25-5.0% Pichia pastoris FermentExtract—1.0-25% Pichia pastoris/Resveratrol Ferment Extract—0.50-5.0%Xylitylglucoside—0.10-5.0% Anhydroxylitol—0.10-5.0% Xylitol—0.10-5.0%L-Carnosine—0.10-5.0%

In further embodiments, the composition comprises some or all of thefollowing ingredients: aqua; bulbine frutescens, caprylic/caprictriglyceride, glycerin, stearic acid, d-panthenol, cetearyl alcohol,lanolin oil, phosphatidylserine, cetyl phosphate; tocopheryl acetate;cetearyl ethylhexanoate, isopropyl myristate, sodium polyacrylate,mineral oil, trideceth-6, triterpenic glycosides of Centella asiatica,alpha bisabolol; phenoxyethanol, potassium hydroxide, xanthan gum,oleuropein, methylhydroxybenzoate, butylated hydroxy toluene; fragrance,and retinyl palmitate. In yet further embodiments, the topicalcomposition may also comprise, consist essentially of, or consist of oneor more of the following ingredients listed on Table 2 in addition to,or instead of, the ingredients listed above:

TABLE 2 Water—q.s., which in on embodiment acts as a solvent ArachidylAlcohol—0.10-5.0%, which in one embodiment acts as an Emulsifier BehenylAlcohol—0.10-5.0%, which in one embodiment acts as an EmulsifierArachidyl Glucoside—0.10-5.0%, which in one embodiment acts as anemulsifier Dimethicone—0.25-3.0%, which in one embodiment acts as anemollient Olive Extract (e.g., oil)—0.25-5.0%, which in one embodimentacts as an emollient Phenoxyethanol—0.50-1.25%, which in one embodimentacts as a preservative Disodium EDTA—0.02-0.30%, which in one embodimentacts as a chelating Agent Carbomer—0.05-1.0%, which in one embodimentacts as a thickening Agent Polyacrylate-13—0.10-5.0%, which in oneembodiment acts as a thickener and/or stabilizerPolyisobutene—0.10-5.0%, which in one embodiment acts as an emollientand/or a stabilizer Polysorbate 20—0.10-5.0%, which in one embodimentacts as an emulsifier Potassium Sorbate—0.05-1.0%, which in oneembodiment acts as a preservative Ethylhexylglycerin—0.05-1.0%, which inone embodiment acts as a preservative

Standard extraction processes can be used to manufacture the olive,Bulbine extract and Centella extracts. Maceration, cold-pressing,solvent extraction, and distillation, or combinations therefore, areused in some embodiments. In one embodiment, extracts of olive leaf areproduced by extracting in ethanol, drying, and sifting through, forexample, a 25 mesh screen. In one embodiment, bulbine leaves areexpressed and filtered to produce an extract. In one embodiment,Centella is extracted in water and alcohol and sifted through, forexample, an 80 mesh screen. In some embodiments, further isolation andpurification steps are used.

Examples of Forms, Tapes and Support Structures

Several embodiments of the topical compositions described herein can bein the form of an ointment, cream, lotion, paste, gel, spray, aerosol,powder, oil, or combinations thereof. In some embodiments, the inventioncomprises a device that compartmentalizes the ingredients until time ofapplication. For example, in one embodiment, one or more ingredients areseparated from other ingredients until a user combines them. In someembodiments, a dual chamber or multi-chamber device is used to holdand/or apply the topical composition.

In one embodiment, the invention comprises a kit that includes extractsof Centella asiatica, Bulbine frutescens, olive, and silicone. In otherembodiments, the compositions described herein can be provided on apatch for e.g., controlled time release. In yet other embodiments, thecompositions described herein can be formulated into capsules, tincturesor other forms for oral consumption (e.g., compositions comprisingextracts of Bulbine, Centella, olive, and/or phosphatidylserine, andoptionally other plant extracts and vitamins), and may be particularlywell-suited in a nutraceutical regime that is combined with a topicalskin care plan.

In one embodiment, a topical application to minimize scarring comprisingsupport, hydration, collagen maturation and controlled inflammation isprovided. In one embodiment, a tape or other support structure (e.g.,bandage, patch. etc.) is applied to a wound or scar. Supporting a scar,particularly a long scar, in areas where vector forces continually pullon the scar, is provided in some embodiments. For example, in thepresternal chest area, forces may be generated on the scar from neckmovements, shoulder movements, arm movements and additionally from theweight of breasts in some women. The direct response to such vectorforces is increased production of collagen in an effort to keep thewound closed. Thus, in some embodiments, a tape may be particularlyhelpful in scar treatment. In some embodiments, using agents such asVitamin E (especially when used early) can cause major skinsensitivities and have a collagenase-like effect, which weakens the scarand can have adverse consequences with stretching and even opening ofthe scars. Thus in embodiment of the invention, the composition does notinclude Vitamin E and/or any agent having collagenase-like activity.

In one embodiment, a scar support comprising a microporous tape isprovided. In one embodiment, the tape is applied longitudinally alongthe scar path and not at right angles to facilitate consistent support.In one embodiment, the tape is left in place for days until itspontaneously separates. Premature removal may result in skin strippingwhich sets up inflammation with negative consequences on the scar.Although small areas of scars may not need support, some small scars dovery well with support. For example, cuts on fingers are continuallystressed with forces, and thus applying a single layer of microporoustape supports the scar, avoids maceration as seen with common plasters,and allows the application of additional agents to the tape surface tospeed up the maturation process. In one embodiment, the tape comprisesthin layers that can be applied over one another, thereby obviating theneed to remove the tape. In one embodiment, one or more layers aredissolvable. Support structures (such as tape), according to severalembodiments, comprise polyethylene, hydrogel, silicones, cotton, silk,polyester, fabric, foam, plastic, elastic, various adhesives, collagen,etc. and combinations thereof.

In one embodiment, a tape (or other support structure) is applied to thelength of the scar and the topical composition is applied to the tape.The application of the tape and gel may be commenced as soon asconvenient after the wound has been formed. In one embodiment, the tapeis a microporous tape that permits contact of the topical compositionwith the skin when the topical composition is applied over the tape. Insome embodiments, the topical composition is applied to the skin beforethe tape is placed. In that situation, the tape may be porous or not. Insome embodiments, the topical composition comprising extracts ofBulbine, Centella, olive, and silicone achieves a short-term stickyconsistency that works synergistically with the tape. In one embodiment,the tape saturated with the topical composition (e.g., gel) adheres tothe wound more effectively than previous formulations.

In one embodiment, a user is instructed to use a tape (or other supportstructure) and keep the tape in place during bathing. The tape need onlybe replaced once spontaneous separation takes place (e.g., 3-5 days).Gel may be applied to the surface of the tape twice a day and theroutine is continued until scar maturation (e.g., white color) takesplace. In one embodiment, the tape component may be stopped anywherefrom six weeks of application if the scar is seen to be maturing well,and gel is then applied directly to the scar. In one embodiment, thetopical compositions described herein is effective within 6 weeks ofusing the tape, as compared to longer periods (e.g., 6 months) of usingthe tape with other compositions. In one embodiment, the topicalcomposition (e.g., gel) is used under the support structure (e.g.,tape). For example, gel may be applied as a “worm-like” application tothe surface of a scar or wound, not massaged, and covered completely bythe tape which overlaps non-affected skin on all sides ensuringadhesiveness. The user may bathe with tape and gel in place, and afterapproximately three days, the tape may be removed (e.g., while bathing).Subsequently, the scar or wound is washed and the gel re-applied andthen covered with new tape. The user is instructed to continue thistreatment until the color of damaged skin whitens.

In a further embodiment, the topical composition (e.g., gel) may beapplied as a narrow thin film-like application directly and limited tothe scar surface keeping surrounding areas free from gel ensuring goodadhesion of tape to the gel applied scar surface. This routine isrepeated at every dressing/tape change. The user may bathe with tape andgel in place, and after approximately three days, the tape may beremoved (e.g., while bathing). Subsequently, the scar or wound is washedand the gel re-applied and then covered with new tape. After 4-6 weeks,according to one embodiment, the tape application may be discontinuedand the user is instructed to use the gel directly on the scar surfacetwice a day until scar maturation is observed by flattening and colorchange (pink to white color in white skin, dark black/brown tolight/very light brown in darker skin).

In a further embodiment, the topical composition (e.g., gel) may beapplied directly to the scar surface twice a day after 2, 3, or 4 weeksof supportive tape therapy.

In several embodiments, a tape or other support structure is not neededto treat a scar because the consistency of the topical compositionprovides sufficient support. For example, in one embodiment, the topicalcomposition heals with the formation of a barrier film that protects thescar from environmental influences and ensures a certain amount ofsupport to the scar. In one embodiment, the topical composition forms athin film or crust when dry. This provides a certain amount of supportto the scar and serves as a barrier from outside contamination,irritation from the sun, and cosmetics. Several embodiments of thetopical composition described herein can advantageously be used withoutany tape or supporting structure because the synergic effect of theBulbine, Centella, oleuropein and optionally silicone create aself-supporting barrier that does not require additional support. Inseveral embodiments, a tape is not needed because non-scar conditionsare treated, where support may not be needed.

In some embodiments, physical stimulation, such as by massage, needle(derma) rollers, is also incorporated as part of the regime for treatingdamaged skin. In one embodiment, a pre-treatment is provided prior toapplication of the topical compositions described herein. Thepre-treatment includes, but is not limited to, exfoliation, physicalstimulation, and energy-based stimulation (e.g., light, radiofrequency,ultrasound, microwave, etc.). The pre-treatment may be helpful toincrease the absorption of the topical composition and/or worksynergistically with the topical composition. The pre-treatmentmodalities described herein may also be used during and/orpost-treatment.

Examples of Uses and Timing

In one embodiment, the topical compositions disclosed herein are usedfor controlling scar outcome and are applied at the time of woundingwhen the trigger for the sequence of healing begins or as soonthereafter as possible. In one embodiment, the topical composition iseffective on scars that are several weeks, months or years old. In oneembodiment, the topical composition prevents undesirable scarring. Inone embodiment, the topical composition reduces one or more of thefollowing characteristics of a scar by at least 25%, 50%, or 75%, ascompared to a wound that is not treated with the composition: scarroughness, intensity of color, scar elevation and/or scar size. In someembodiments, the topical compositions may be helpful with keloidscarring, although the etiology of keloid scarring are generally verydifferent from non-keloid scarring, and formulation adjustments may beneeded.

In one embodiment, a method of treating a scar is provided, wherein themethod comprises applying a topical composition disclosed herein to thescar at the time of provisional scar matrix formation to effectsubsequent matrix dissolution and maturation. In one embodiment thetreatment of the scar is commenced immediately following wound closure(e.g., at the time of surgery or injury), or within a day or twothereafter. In another embodiment, the wound is treated within 1-4 weeksof wound occurrence. In several embodiments, the invention comprisesapplying the topical composition to a scar that is weeks, months oryears old to improve the appearance of the scar.

In some embodiments, the topical compositions provided herein areapplied to scars or other undesirable marks on the skin, such ascellulite, stretch marks, wrinkles or age spots to improve theappearance of same. In other embodiments, the topical compositionprevents the occurrence of cellulite, stretch marks, wrinkles, or agespots, and may be used on healthy or non-damaged skin. In someembodiments, because of the effects on collagen, the topicalcompositions help with skin laxity and are useful for skin tightening.

In several embodiments, the topical compositions provided herein areused to treat aged skin. In one embodiment, the treatment would be asfollows: each morning a collagen booster such as phosphatidylserine(optionally combined with other ingredients, such as Bulbine forhydration) is applied to the skin together with an antioxidant and a sunprotection cream. In the evening, the collagen booster(phosphatidylserine) is applied to the skin together with extracts ofBulbine, Centella, olive and optionally silicone and/or otheringredients. In one embodiment, a method of treating aged skin isprovided, wherein the aged skin is characterized by a shortage ofcollagen and irregular collagen the fibrils of which are clumped oraggregated in nature. Young skin, on the other hand, is typicallyassociated with uniform collagen fibers and good amounts of type 1collagen. Several embodiments of the invention (i) stimulate of theformation of procollagen (e.g., because of the effect of thephosphatidylserine), (ii) stimulate of the formation of type 1 collagen(e.g., because of the Centella asiatica), (iii) promote uniformly spacedcollagen (e.g., due to the effect of the Bulbine frutescens), and/or(iv) mop up of free radicals that are associated with aging (e.g., dueto the oleuropein and the Centella asiatica).

In one embodiment, the invention comprises a method of reducing freeradicals and matrixmetalloproteinases MMP, e.g., type 1, wherein themethod comprises: identifying damaged skin, applying (or instructingapplication of) a topical composition described herein to said damagedskin, thereby reducing free radicals.

In one embodiment, the invention comprises a method of increasing theformation of pro-collagen and/or type 1 collagen, wherein the methodcomprises: identifying damaged skin, applying (or instructingapplication of) a topical composition described herein to said damagedskin, thereby forming pro-collagen and/or type 1 collagen.

In one embodiment, the invention comprises a method of promotinguniformly spaced collagen, wherein the method comprises: identifyingdamaged skin, applying (or instructing application of) a topicalcomposition described herein to said damaged skin, thereby promotinguniformly spaced collagen.

In one embodiment, the combination of Centella asiatica, Bulbinefrutescens and oleuropein promote an increase in collagen and itssequential modulation to a well-structured form. In the context ofcollagen modulation, particularly when considering anti-agingintervention, the Centella extract, Bulbine extract, and oleuropein maybe used in conjunction with phosphatidylserine, wherein thephosphatidylserine promotes the formation of procollagen, a collagenprecursor and decreases the levels of MMP 1 which breaks down collagenand extracellular matrix components, characteristic of photodamage. Thisnew collagen is then acted on by the combination of Centella extract,Bulbine extract, and oleuropein to induce maturation of the collagen.This embodiment of a topical composition acts synergistically to achieveimportant anti-aging benefits.

In one embodiment, the combination of Centella extract, Bulbine extract,oleuropein and phosphatidylserine may be used as an adjunct to anti-acnetreatment. In this embodiment, the topical composition is used tominimize the eventual scarring resultant from the acne. In oneembodiment, the topical composition is used once the acute pustularphase of the acne is ending and the inflammatory phase has started. Thetopical composition (e.g., in gel form) is applied to the individualacne lesions to promote healing, decrease inflammation and improve thefinal outcome in terms of scarring. There may well be beneficial effectsin the early pustular phases of acne due to the antibacterial andanti-inflammatory effects of oleuropein and the healing effects ofCentella, Bulbine and olive extracts, but, in one embodiment, the mainindication in patients with acne would be for its use in diminishingscarring.

In several embodiments, the topical compositions described herein may beused to promote circulation and/or act as an anti-oxidant. Topicalcompositions according to several embodiments are useful in thetreatment of dermal or subdermal infections. In one embodiment, varicoseveins and/or spider veins are treated. In other embodiments, rosaceaeczema, and/or psoriasis are treated. In several embodiments, use of thetopical composition will reduce the scarring and pitting associated withchicken pox. In several embodiments, use of the topical composition isuseful for insect bites and allergic reactions. In several embodiments,the compositions are used to treat burns. In several embodiments, suchas burns, wounds or painful inflammation, the composition mayadditionally include or be administered with an analgesic (such aslidocaine, menthol, methyl salicylate, camphor, and/or capsaicin). Insome embodiments, because pain-related neurotransmitters may generatefibrosis if they are continuously stimulated, the compositions disclosedherein comprise ingredients that reduce such neurotransmission. In oneembodiment, sterols (e.g., plant sterols, β-sitosterols), flavonoids,alkaloids, etc. are provided to modulate neurotransmission to reducepain and fibrosis. In one embodiment, the topical compositions disclosedherein are used before, during and/or following cosmetic surgery, orother surgery, to facilitate recovery and appearance. For example, thecompositions disclosed herein may be used before, during or afterchemical peels, laser resurfacing, energy-based aesthetic therapies(such as microwave, radiofrequency and ultrasound), filler injections,skin shavings, mole removals, biopsies and hair removal. Prior treatmentwith the topical composition may help prime the skin for later distress(e.g., due to a cosmetic procedure).

In several embodiments, the topical compositions described herein areformulated as moisturizers, body washes, soap, lotions, serums, eyecreams, gels, sunscreens, bronzers, powders, nail care, hair care,foundation, blush, lip color, eye color and other cosmetics. In severalembodiments, the topical compositions provided herein are useful forinclusion in shampoos, conditioners, and other hair treatments. Inseveral embodiments, most or all of the ingredients are natural ororganic. In many embodiments, the ingredients are non-comedogenic.

According to several embodiments, the present invention is primarilyconcerned with the treatment of human subjects, but the invention mayalso be carried out on non-human subjects, particularly mammaliansubjects such as dogs, cats, livestock and horses for veterinarypurposes. While subjects may be of any suitable age, the subjects are,in some embodiments, adult or geriatric subjects.

In several embodiments, the topical compositions described herein havesubdermal effects. In one embodiment, the topical compositions modulatesignaling mechanisms that interconnect the many layers of the dermiswith the outer epidermal layer. In one embodiment, the topicalcompositions described herein modulate surface keratinocytes, which inturn orchestrate and initiate signaling events. In one embodiment, thetopical compositions, with or without a scar tape, exhibit one or moreof the following effects: SMAD7 inhibition of signaling to TGF-β,connexin 43 antagonism, connective tissue growth factor targeting,anti-SMAD2/3/4 complex, decreasing cadherin activation, andmyofibroblast phenotype induction inhibition.

Several embodiments of the invention cause a decreased activation ofkeratinocyte signaling by mimicking stratum corneum function (hydration)resulting in decreased production of IL-1β (and probably other cytokinesyet to be identified), increased production of antifibrotic tumornecrosis factor (TNF)-α clearing the extracellular matrix remnants andan increase in TGF-β3 via stimulation of the SMAD7 signaling mechanism.This may result in extracellular matrix remodeling with lessinflammation, decreased collagen production, and balanced proteaseactivity, collectively encouraging scar maturation.

Several embodiments of the invention prevent hypertrophic scar formationby, for example, simultaneous stimulation of SMAD7 expression andactivation of proteasome degradation of SMAD3/4 signals. In oneembodiment, plant-based phenols or other olive extracts play a role instimulation. In one embodiment, oleuropein stimulates proteasomes to mopup extracellular fragments.

A short time (e.g., within an hour) after wounding, cyclooxygenase-2(COX-2) enzyme may be activated to synthesize prostaglandins.Metabolites and enzymes of the arachidonic acid cascade, including theCOX-2 enzyme and its enzymatic product prostaglandin E2 may mediate theinflammatory response. Thus, several embodiments of the inventioninhibit this inflammatory pathway, thereby reducing scar formationand/or treating damaged skin.

Maturation of the inflammatory process may involve a progressiveincrease in TGF-β3. This growth factor isoform appears to be involved incessation of matrix deposition. TGF-β3 reduces fibronectin and collagendeposition and is considered potently antifibrotic. Several embodimentsof the invention modulate TGF-β3 levels. In one embodiment, Centellaextracts increase TGF-β3 levels. In one embodiment, the topicalcompositions described herein contain other agents that modulate TGF-β3activity, including recombinant TGF-β3.

Several embodiments of the invention, including but not limited tocompositions comprising Bulbine, Centella and phenolic compounds (e.g.,olive extracts), exhibit one or more of the following effects: increaseSMAD7, increase TGF-β3, decrease TGF-β1, decrease COX-2, increaseproteasome activation, and display potent antioxidant effects, andprovide synergistic treatment of scars and other damaged skin.

The term “treat” as used herein shall be given its ordinary meaning andshall also include any type of treatment that imparts a benefit to asubject, e.g., delaying or retarding the progression of the condition.The condition, according to several embodiments, may be associated withaging, ultraviolet light exposure, wounds, surgery, infection, allergy,autoimmune effects, etc.

The term “pharmaceutically acceptable” as used herein shall be given itsordinary meaning and shall also include a compound or compositionsuitable for administration to a subject to achieve the treatmentsdescribed herein, without unduly deleterious side effects in light ofthe severity of the disease and necessity of the treatment.

The term “extract” as used herein shall be given its ordinary meaningand shall also include one or more active agents or compounds (which mayfurther include non-active components) obtained or isolated from aplant. Extracts may also include modified or synthetic versions ofnaturally-occurring compounds. Extracts may be, for example,mechanically or chemically purified or isolated from a plant source. Theterms agents and ingredients may be used interchangeably.

The term “composition” as used herein shall be given its ordinarymeaning and shall also include combinations or mixtures of one or moreingredients. A composition may include both active and inactiveingredients. Compositions may be oral, topical, or suitable forinjection or other application. The terms compositions, medicaments andformulations may be used interchangeably.

Several embodiments of the invention will now be described by way ofexample with reference to the following non-limiting examples.

Example 1

Sixty patients each having a scar following simple skin excisions formedpart of this example. Thirty of the patients had their scars treated;thirty had their scars untreated (10 face, 10 limbs, 10 back in eachgroup).

The treated patients were each treated as will be described with oneembodiment of a scar gel of the invention. The scar gel comprised theingredients and percentages as set out in Table 3.

TABLE 3 Description or Ingredient action in one embodiment Aqua destDistilled water Poloxamer Gel Matrix Glycerol-polyethylene glycolSurfactant. Helps in collecting oil oxystearate droplets into aqueousgel matrix Propylene glycol Solvent Dimethicone Oil carrier; SiliconeOleuropein (olive leaf extract) Antiseptic properties (anti-fungal; antibacterial and anti inflammatory Triterpenic fraction of Reducer of Scartissue This converts Centella asiatica collagen III to collagen IPhenoxyethanol Preservative against fungi Methylhydroxy-benzoatePreservative against germs Lactic acid To bring acidity of the productto near skin pH which is lower than 5.5 Bulbine Frutescens Forre-arranging collagen fibrils. Microporous tape Optional Support

In one embodiment, the triterpenic fraction of Centella asiaticacomprises 0.5% m/m of the medicament; the Bulbine Frutescens comprises10.0% m/m of the medicament, and the oleuropein comprises 0.18% to 0.3mass/volume of the medicament.

Patients were randomized to receive either routine postoperative carewith tape alone (bilateral cosmetic cases) (the untreated patients) orcombined tape with topical scar gel or no treatment (routine for smallskin excisions) (the treated patients). Where one side was treated, theside selected for treatment was also randomized (at the end of surgery,the nursing staff drew lots to choose the right or left side fortreatment). All scars were assessed and photographed at follow-up at 1,2, and 6 months following surgery.

In contrast to known management programs, scar management was initiatedin the treated patients immediately following surgery.

For small local excisions of skin tumors, the wounds were left without adressing on the face and gel was applied directly to the site andcontinued twice daily by the patient as long as desired and normally forthe full six month period.

In an effort to combine all recent recommendations for scar assessment,elements of different scales were incorporated into the assessmentparameters. Thus, elements of the Vancouver Scar Scale were incorporatedinto the scale of morphologic features. Patient and observer assessmentcharts were also included in the assessments as previously recommended.

The data were revised into a format compatible with the statisticalprogram using SAS v9. Differences between treated and untreated patientswere determined using the Kruskal/Wallis test with p<0.05 consideredsignificant.

In the patients there were no significant differences apparent one monthafter the operation, the scars were significantly improved after twomonths in the treated versus the untreated group. Over the six monthsthe morphologic grading scores improved only in treated but notuntreated patients.

Scar thickness and regularity of the treated scars were rated as beingsignificantly better than untreated scars, with scar stiffness reachingborderline significance.

Observers rated scar vascularization, pigmentation, thickness, relief,and pliability of the scar. All these parameters were significantlyimproved (p<0.005) in treated patients compared with the parameters ofuntreated patients.

Observers noted scar hypopigmentation, hyperpigmentation, and mixed(hypo/hyperpigmentation) scars in 16 of the treated patients (89%). Thiscompared favorably (p=0.04) with the untreated patients in whom 14/23(61%), 4/23, and 5/23 had hypo-, hyper-, and mixed pigmentation(hypo/hyperpigmentation) scars respectively.

Example II

In another non-limiting example, twenty patients each patient with twoexcisions formed part of this study. Of the two excisions of eachpatient, one was treated and one untreated (10 back, 5 face, 5 limbs).

On the back and limbs the site was covered with microporous tape. Scargel was applied immediately following surgery on to the surface of thetape, saturating it and producing an occlusive type of dressing.Patients were instructed to apply scar gel to the surface of the tapetwice a day morning and night.

The scar assessment was as indicated above. In patients with twoexcisions where one was treated and the other not (Group 1) thedifferences in scar morphology became significantly apparent at 6months. As with Example 1, the treated but not the untreated scarsshowed significant improvement over the 6 months.

Observers rated scar vascularization, pigmentation, thickness, relief,and pliability of the scar. Except for the vascularization rating, allother parameters were significantly improved.

Example III

Ten patients undergoing skin surgery were treated with the scar gel asset out in Table 3. The ten patients had 20 scars following bilateralbreast surgery, one side treated with tape alone, one side treated withtape and gel (5 breast augmentations, 5 breast reductions).

In patients to whom the gel was applied, the scar gel was appliedliberally to the area prior to application of the dressing. The gel wasnot massaged in but was left on the surface to ensure a reasonableamount of gel on the scar surface while the dressing was leftundisturbed for seven to ten days.

In cases where the dressing was changed the following day (breastreduction procedures), scar gel was reapplied to the selected side.Following the dressing change after seven to ten days, patientscontinued with the program for three to six months until the scar wasconsidered mature (nonsymptomatic, white). The scar assessment was asindicated above.

Similar results were found for this group of breast augmentation andreduction patients. Treated scars showed significant morphologicimprovement after two months with borderline significance at 1 and 6months compared to the untreated scars (i.e. the scars treated by tapealone).

Only treated scars showed significant improvement in itchiness, withscar stiffness, thickness, and regularity approaching significance.Observers rated scar vascularization, pigmentation, thickness, relief,and pliability of the scar. Vascularization and pigmentation wereimproved in treated scars with scar thickness, relief, and pliabilityreaching borderline significance.

Early scar control starting at the time of wounding is new in theimprovement of scar outcome. Thus although the application of the scargel can be commenced from seven to fourteen days after surgerypreferably the scar gel is applied at the time of initial dressing atthe end of the surgical procedure or the following day after surgery andas an immediate and continued application to the wound for small localexcisions of skin lesions was applied in all the Examples. Efficacy wasparticularly evident in the patients mentioned in Example III wherethose treated immediately with tape and scar gel had better outcomes inall parameters measured.

Example IV

Thirty patients with varying cosmetic procedures with 50 scars alltreated and compared with historical outcomes for hypertrophic scarring(10 breast augmentations, 10 breast reductions, 10 abdominoplasties).The scars were treated immediately after surgery with the scar gelmentioned in Table 3.

The scar assessment was as indicated above. The results showed thatthese patients who underwent a variety of procedures and showedimprovement in scar morphology over the 6 months of follow-up. Overallmorphology improved in all the groups.

Observers rated scar vascularization, pigmentation, thickness, relief,and pliability of the scar. All these parameters were significantlyimproved (p<0.005) in treated patients compared with the parameters ofuntreated patients. Observers noted scar hyperpigmentation were similarin the treated patients in Example I.

It will be seen therefore that in the important areas of scarassessment, the patients treated in all examples showed statisticallysignificant improvement in all parameters. Morphologic features togetherwith stiffness, thickness, and irregularity in POSA and thickness andrelief in OSA are probably the most important parameters for analysingscar hypertrophy.

A number of patients had undergone previous surgery. The first scars(i.e. from the previous surgery) were compared with those produced bythe new surgical procedure where the scar program was used. In two ofthese cases previous infra-mammary scars were excised in patients whohad undergone reduction surgery elsewhere. The new infra-mammary scarsdemonstrated superior scar outcomes to those of the previous mid-lineand periareolar scars. Morphologic assessment of scars at two months(not one month) were usually (although not always) reasonable predictorsof long-term scar outcome. Predictors of poor outcome of long-termresults appeared to be that of early signs of scar thickening orhypertrophy (Grade 3 morphologic scale).

In the examples set forth above, support by microporous tape may not beneeded, for example in cases where the wound is supported bysubcuticular sutures. In one embodiment, tape is also not needed forsmaller excisions or skin lesions, where tension on the skin is expectedto be much less in these cases. In one embodiment, the invention resultsin a multimodal treatment that results in hydration, controlledinflammation, and collagen maturation in which the ingredients actsynergistically to convert the microporous tape to an occlusiveinteractive. In several embodiments, the combination of ingredients(e.g., Bulbine, Centella and olive extracts, etc.) shows markedimprovement over ingredients that only provide hydration.

One skilled in the art will readily appreciate that embodiments of thepresent invention are well adapted to carry out the objects and obtainthe ends and advantages mentioned, as well as those inherent therein.The present examples along with the methods, procedures, treatments,molecules, and specific ingredients described herein are presentlyrepresentative of several embodiments, and are not intended aslimitations on the scope of the invention. Changes therein and otheruses which are encompassed within the spirit of the invention may bedefined by the scope of the claims.

What is claimed is:
 1. A method for treating damaged skin of a human inneed thereof, said method comprising topically applying at least oneextract of Bulbine frutescens to the damaged skin of the human in needthereof, in an amount from about 9% to about 11% mass per mass of thecomposition; topically applying at least one extract of Centellaasiatica to the damaged skin of the human in need thereof, in an amountfrom about 0.1% to about 2% mass per mass of the composition; topicallyapplying oleuropein to the damaged skin of the human in need thereof, inan amount from about 0.18% to about 0.3% mass per mass of thecomposition; topically applying dimethicone to the damaged skin of thehuman in need thereof, in an amount from about 0.25% to about 3% massper mass of the composition; wherein said extract of Bulbine frutescens,extract of Centella asiatica oleuropein and dimethicone form acomposition which is disposed onto a tape which is topically appliedonto the damaged skin of the human in need thereof.